Allogeneic CAR T-cell therapy for relapsed or refractory multiple myeloma: Results from the UNIVERSAL trial

Therapy with B-cell maturation antigen (BCMA)-directed autologous chimeric antigen receptor (CAR) T-cells has demonstrated encouraging efficacy in patients with relapsed/refractory (R/R) multiple myeloma (MM). However, a number of factors limit the availability of autologous therapies, such as the quantity and quality of cells collected or the extended vein-to-vein time. Allogeneic (allo) cell therapies have been proposed as an alternative, with the aim to overcome manufacturing- and patient-associated challenges.

ALLO-715 is an anti-BCMA allo-CAR T-cell product that, importantly, lacks CD52. This attribute allows for lymphodepletion with the CD52-targeting monoclonal antibody ALLO-647 with no impact on the therapeutic T-cells. Furthermore, ALLO-715 lacks the T-cell receptor alpha constant gene, making patients less susceptible to developing graft-versus-host disease.

During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, Sham Mailankody presented the data from the first-in-human UNIVERSAL study (NCT04093596) of ALLO-715 in combination with ALLO-647 lymphodepletion in patients with R/R MM.¹ The Multiple Myeloma Hub is pleased to present a summary.

Study design

Patients with MM who were R/R to their last prior therapy were eligible for enrollment if they met the following criteria:

• Three or more prior therapies with an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 therapy
• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
• Absence of donor-specific antibodies
• Bridging therapy was not allowed.

The UNIVERSAL study schema is outlined in Figure 1. The primary endpoints of the study were safety and tolerability, and secondary endpoints included:

• Recommended phase II dose of ALLO-715 and ALLO-647 lymphodepletion regimen
• Overall response rate, duration of response, progression-free survival, and measurable residual disease
• Cellular kinetics of ALLO-715
• Pharmacokinetic profile of ALLO-647.

CAR, chimeric antigen receptor; D, day; M, month.
*FCA conditioning with fludarabine, cyclophosphamide and ALLO-647; †CA conditioning with cyclophosphamide and ALLO-647.

Results

• Median follow-up: 3.2 months.
• At the data cut-off, 31 and 26 patients comprised the safety and efficacy populations, respectively.

Patient characteristics

The study population (N = 31) was largely comprised of patients with heavily pretreated, advanced, refractory stage MM (Table 1).

Table 1. Patient characteristics¹

Auto-SCT, autologous stem cell transplant; ECOG, Eastern Cooperative Oncology Group; ISS, International Scoring System. *del17p, t(4;14), t(14;16); †received therapy with ≥2 immunomodulatory drugs, ≥2 proteasome inhibitors, and a CD38 monoclonal antibody.
Characteristics, % unless stated otherwise	Safety population (N = 31)
Median age, years (range)	65 (46–76)
Male	61
ECOG performance score
0	48
1	52
ISS stage ≥2	74
High-risk cytogenetics*	48
Median prior lines of therapy, n	5
Prior auto-SCT	94
Penta-exposed†	94

 Efficacy

From the early efficacy data, no objective responses were observed at dose level 1, but response rates improved in patients receiving dose level 3 and FCA conditioning (Table 2). Of the six patients who achieved a very good partial response or better, five were analyzed for measurable residual disease, all of whom were determined negative by multicolor flow cytometry.

Table 2. Response rates to variable doses of ALLO-715¹

CA, conditioning with cyclophosphamide and ALLO-647; DL, dose level; FCA, conditioning with fludarabine, cyclophosphamide, and ALLO-647; M, million; ORR, overall response rate; VGPR, very good partial response.
ALLO-715 cell dose and LD regimen	FCA					CA
	DL2 (160M)	DL3 (320M)			DL4 (480M)	DL3 (320M)
	Low ALLO-647 (n = 4)	Low ALLO-647 (n = 6)	High ALLO-647 (n = 4)	All ALLO-647 (n = 10)	Low ALLO-647 (n = 3)	Low ALLO-647 (n = 3)
ORR, %	50	50	75	60	33	67
≥VGPR, %	25	50	25	40	—	33

Safety

The combination of ALLO-715 and ALLO-647 exhibited a promising safety profile, with no graft-versus-host disease or immune effector cell‐associated neurotoxicity syndrome reported. Furthermore, cytokine release syndrome was well managed with tocilizumab and steroids, and infusion-related reactions were all low grade (1 or 2). Grade ≥3 adverse events were observed in 19% of patients and there was one Grade 5 event resulting from progressive myeloma in the conditioning with cyclophosphamide and ALLO-647 cohort.

CAR T-cell expansion

ALLO-715 CAR T-cell expansion was observed by Day 7, increased respective of dose, and persisted for 4 months in patients who received dose level 3.

Conclusion

The UNIVERSAL trial represents the first clinical trial to evaluate an allo-BCMA-targeted CAR T-cell product. Preliminary data suggest that ALLO-715 demonstrates a promising efficacy and safety profile in patients with heavily pretreated R/R MM. Enrollment for the planned evaluation of increasing cell doses and optimization of lymphodepletion regimens is ongoing.

Allo-CAR T-cell therapy is not limited to the MM setting. The CD19-directed therapy, ALLO-501, appears well tolerated and demonstrated encouraging short-term preliminary efficacy in patients with R/R diffuse large B-cell lymphoma or follicular lymphoma. You can read more here.